An Interaction between Brain-Derived Neurotrophic Factor and Stress-Related Glucocorticoids in the Pathophysiology of Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(3), P. 1596 - 1596

Published: Jan. 27, 2024

Both the brain-derived neurotrophic factor (BDNF) and glucocorticoids (GCs) play multiple roles in various aspects of neurons, including cell survival synaptic function. BDNF its receptor TrkB are extensively expressed neurons central nervous system (CNS), contribution BDNF/TrkB to neuronal function is evident; thus, downregulation has been considered be involved pathogenesis Alzheimer’s disease (AD). GCs, stress-related molecules, glucocorticoid receptors (GRs) also associated with AD addition mental disorders such as depression. Importantly, a growing body evidence suggests close relationship between BDNF/TrkB-mediated signaling GCs/GR CNS. Here, we introduce current studies on interaction stress CNS discuss their involvement pathophysiology AD.

Language: Английский

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Possible Role of Fibrinaloid Microclots in Postural Orthostatic Tachycardia Syndrome (POTS): Focus on Long COVID

Journal of Personalized Medicine, Journal Year: 2024, Volume and Issue: 14(2), P. 170 - 170

Published: Jan. 31, 2024

Postural orthostatic tachycardia syndrome (POTS) is a common accompaniment of variety chronic, inflammatory diseases, including long COVID, as are small, insoluble, 'fibrinaloid' microclots. We here develop the argument, with accompanying evidence, that fibrinaloid microclots, through their ability to block flow blood microcapillaries and thus cause tissue hypoxia, not simply correlated but in fact, by preceding it, may be chief intermediary POTS, which body's exaggerated 'physiological' response hypoxia. Similar reasoning accounts for symptoms bundled under term 'fatigue'. Amyloids known membrane disruptors, when targets nerve membranes, this can explain neurotoxicity hence autonomic nervous system dysfunction contributes POTS. Taken together view, we indicate microclots serve link POTS fatigue COVID manner at once both mechanistic explanatory. This has clear implications treatment such diseases.

Language: Английский

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Mitochondrial Transportation, Transplantation, and Subsequent Immune Response in Alzheimer’s Disease: An Update

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: 61(9), P. 7151 - 7167

Published: Feb. 17, 2024

Language: Английский

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Physical Exercise Counteracts Aging-Associated White Matter Demyelination Causing Cognitive Decline

Aging and Disease, Journal Year: 2024, Volume and Issue: 15(5), P. 2136 - 2136

Published: Jan. 1, 2024

In the central nervous system, oligodendrocytes wrap around neuronal axons to form myelin, an insulating layer or sheath that allows for efficient conductance of action potentials. addition structural insulation, myelin provides encased with nutrient, metabolic and defensive support. Demyelination, loss, can therefore cause axonal dysfunction, leading neurological impairment disease. Alzheimer's disease (AD), progressive white matter demyelination is acknowledged as one earliest pathologies preceding symptom onset. Unfortunately, current pharmacotherapy slowing promoting remyelination in AD nonexistent. Exercise recognized its wide-ranging benefits human health, including improved mental health prevention lifestyle-related diseases. Mounting evidence suggests contribution physical activity delaying progression dementia elderly populations. Recent mechanistic studies have shown exercise facilitates myelination brain through vitalization intrinsic pro-myelination cues, such increased neurotrophic factors electrical activity. this review, we summarize discuss potential on counteracting aging-associated demyelination, which causes cognitive decline AD. We highlight need further basic clinical research investigations topic establish novel approaches healthy aging.

Language: Английский

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Alzheimer-mutant γ-secretase complexes stall amyloid β-peptide production

eLife, Journal Year: 2025, Volume and Issue: 13

Published: Feb. 11, 2025

Missense mutations in the amyloid precursor protein (APP) and presenilin-1 (PSEN1) cause early-onset familial Alzheimer’s disease (FAD) alter proteolytic production of secreted 38-to-43-residue β-peptides (Aβ) by PSEN1-containing γ-secretase complex, ostensibly supporting hypothesis pathogenesis. However, proteolysis APP substrate is processive, involving initial endoproteolysis to produce long Aβ peptides 48 or 49 residues followed carboxypeptidase trimming mostly tripeptide increments. We recently reported evidence that FAD PSEN1 deficiencies early steps processive C99 this results from stalled enzyme-substrate and/or enzyme-intermediate complexes. These complexes triggered synaptic degeneration a Caenorhabditis elegans model independently production. Here, we conducted full quantitative analysis all events on with six additional found are deficient multiple processing steps. only one these (F386S) was certain but not endoproteolysis. Fluorescence lifetime imaging microscopy intact cells revealed lead enzyme-substrate/intermediate The F386S mutation, however, does so Aβ-rich regions cells, C99-rich regions, consistent mutant enzyme intermediates. findings provide further stabilized process rather than products as pathogenic trigger.

Language: Английский

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Individual bioenergetic capacity as a potential source of resilience to Alzheimer’s disease

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 24, 2025

Impaired glucose uptake in the brain is an early presymptomatic manifestation of Alzheimer's disease (AD), with symptom-free periods varying duration that likely reflect individual differences metabolic resilience. We propose a systemic "bioenergetic capacity", ability to maintain energy homeostasis under pathological conditions. Using fasting serum acylcarnitine profiles from AD Neuroimaging Initiative as blood-based readout for this capacity, we identified subgroups distinct clinical and biomarker presentations AD. Our data suggests improving beta-oxidation efficiency can decelerate bioenergetic aging progression. The estimated treatment effects targeting capacity were comparable those recently approved anti-amyloid therapies, particularly individuals specific mitochondrial genotypes linked succinylcarnitine metabolism. Taken together, our findings provide evidence therapeutically enhancing health may reduce risk symptomatic Furthermore, monitoring via blood measurements be achieved using existing assays. Bioenergetic balance stress, monitored profiles. Improving slow

Language: Английский

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Once upon a time, the Amyloid Cascade Hypothesis

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 93, P. 102161 - 102161

Published: Dec. 6, 2023

Recent trials with monoclonal antibodies targeting amyloid-β (Aβ) in Alzheimer's disease (AD) have sparked a renewed interest disease-modifying therapies. Despite their promise, these leave the issue open and posit some doubts about validity of Amyloid Cascade Hypothesis (ACH). While scores neurocognitive tests improved upon treatment, real-world clinical benefits were minimal. This Viewpoint discusses additional, often overlooked findings from trials. We also emphasize multifactorial nature AD need for broader research perspective beyond simplistic model provided by ACH.

Language: Английский

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More failure with solanezumab – this time in preclinical Alzheimer’s disease

Expert Opinion on Biological Therapy, Journal Year: 2024, Volume and Issue: 24(3), P. 119 - 123

Published: Feb. 28, 2024

There is no cure for Alzheimer's disease, which the sixth leading cause of death in USA. Lecanemab anti-Aβ monoclonal antibody approved treatment early disease but only marginally effective. Other antibodies are being developed including solanezumab.

Language: Английский

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Considering challenges for the new Alzheimer's drugs: Clinical, population, and health system perspectives

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(9), P. 6639 - 6646

Published: Aug. 6, 2024

Recent approvals of amyloid immunotherapy drugs for early Alzheimer's disease (AD) have been highly controversial. In this piece, we consider challenges from the clinical, population health, and health systems perspectives to role that new AD might be expected play, now in future, alleviating morbidity caused by population. Clinically, short-term effects are small, adverse events frequent, treatment regimens burdensome, and, crucially, long-term unknown. At a level, there is always likely trade-off between breadth access magnitude benefit any given individual. system roll out even only narrowly-defined patient groups will involve considerable resources identify treat eligible patients, with profound opportunity costs. Our considered view on current evidence each perspective imagining foreseeable future which significantly alleviates at scale. HIGHLIGHTS: met excitement but also controversy. Trial concerning, Results trial cohorts may not generalize broader, more complex patients. Significant resource requirements eligibility assessment drug administration. Use "presymptomatic" populations supported evidence.

Language: Английский

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Biofilm-camouflaged Prussian blue synergistic mitochondrial mass enhancement for Alzheimer's disease based on Cu2+ chelation and photothermal therapy

Journal of Controlled Release, Journal Year: 2024, Volume and Issue: 375, P. 269 - 284

Published: Sept. 13, 2024

Language: Английский

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